When the usual treatments are not enough
It is discouraging to try a medication, wait weeks, and still feel stuck. It is also common, and it is not the end of the road. Mayo Clinic notes that antidepressants or psychotherapy ease symptoms for most people, but with treatment-resistant depression, standard treatments may not help much, or symptoms improve only to return. NIMH describes treatment-resistant depression as not getting better after trying at least two antidepressants.
If you have reached this point, Mayo Clinic's message is not to lose hope: you and your doctor may simply not have found the right dose, medication or combination yet. The options below exist precisely because the first ones do not work for everyone.
First, take a fresh look
Before adding new treatments, Mayo Clinic suggests a careful review with a specialist, such as a psychiatrist, that considers:
- How you responded to each medication and therapy you have tried, and for how long
- Every medicine you take, including nonprescription drugs and herbal supplements
- Whether medications have been taken as prescribed
- Physical conditions that can cause or worsen depression, such as thyroid disorders, chronic pain or heart problems
- Whether another condition, such as bipolar disorder or a long-term low-grade depression, is part of the picture
- Alcohol or drug use, which Mayo Clinic notes can worsen depression and make it harder to treat
Bring a written list of what you have tried, the doses if you know them, how long you took each, and what happened. It saves time and avoids repeating something that already failed.
Medication adjustments
Mayo Clinic describes several steps a prescriber may discuss: giving a medicine more time (most take four to eight weeks), increasing the dose if appropriate, switching antidepressants, adding a second antidepressant, or adding a medicine usually used for another condition, an approach called augmentation. NIMH notes augmentation may involve an antipsychotic or anticonvulsant medication. Mayo Clinic also mentions pharmacogenetic tests, which can give clues about how your body processes some medications but are not a sure way to show what will work and are not always covered by insurance. Do not change a dose on your own; talk with your prescriber before changing anything.
A different kind of therapy
If therapy has not helped, Mayo Clinic suggests talking with your therapist about a different approach, or seeing someone else. It also notes that for many people, therapy combined with medication works best. Approaches it lists for hard-to-treat depression include cognitive behavioral therapy, acceptance and commitment therapy, interpersonal therapy, family or couples therapy, group therapy and behavioral activation. Types of Therapy for Anxiety and Depression, Explained describes them.
Esketamine nasal spray
Esketamine (Spravato) is an FDA-approved medication for treatment-resistant depression. NIMH notes it often acts rapidly, typically within a couple of hours. According to its current FDA-approved label (revised March 2026), it is approved for adults with treatment-resistant depression either on its own or together with an oral antidepressant, and, with an oral antidepressant, for adults with major depression who have acute suicidal thoughts or behavior.
It is given only under supervision. MedlinePlus explains that you use the spray yourself in a medical facility, and are monitored before, during and for at least two hours afterward. You need someone to drive you home and should not drive until the next day after a restful night's sleep. The label's boxed warning covers sedation, dissociation (feeling disconnected from your body, thoughts or surroundings), breathing problems, abuse and misuse, and suicidal thoughts in young people, which is why it is available only through a restricted program called the SPRAVATO REMS. It can also raise blood pressure for a few hours.
Brain stimulation therapies
NIMH explains that brain stimulation is usually considered after other treatments, and that the plan usually still includes psychotherapy, medication or both. The main options:
- Repetitive transcranial magnetic stimulation (rTMS): a coil held against the head sends magnetic pulses to an area involved in mood. No anesthesia is needed and it can be done in an office. NIMH describes a typical course as daily sessions five days a week for four to six weeks, with faster accelerated schedules now cleared. Side effects are usually mild, such as scalp discomfort or headache.
- Electroconvulsive therapy (ECT): done under brief general anesthesia with a muscle relaxant. NIMH notes it has the longest history of use for depression, usually takes effect within the first week, and is typically given three times a week, often for 6 to 12 treatments. Memory problems around the time of treatment can occur and usually improve over the following days and weeks; electrode placement and pulse width affect that risk.
- Vagus nerve stimulation (VNS): an implanted device stimulates a nerve in the neck. The FDA approved it in 2005 for adults whose severe or recurrent depression has lasted two years or more and has not eased after at least four treatments. NIMH notes it is not a first-line treatment and study results have been mixed.
NIMH adds that brain stimulation is sometimes used earlier when severe depression has become life-threatening, for example when someone has stopped eating or drinking or is at high risk of suicide. Mayo Clinic advises checking whether your insurance covers a recommended treatment; How Much Does Therapy Cost in Michigan? covers coverage questions.
Keeping going in the meantime
Mayo Clinic's advice is not to settle for a treatment that only partly helps or that causes side effects you cannot tolerate. Ongoing therapy can be a steady place while medical options are sorted out. Dr. Lehmann does not prescribe or provide these medical treatments, but depression therapy with her can continue alongside the care of a psychiatrist. Finding a Psychiatrist or Prescriber for Medication in Michigan explains where to start.